Abstract Lack of progress in curing metastatic breast cancer is due to a number of fundamental treatment barriers. These include insufficient knowledge of therapeutic vulnerabilities, lack of reliable predictive biomarkers, inability to target common tumor suppressor gene loss, inability to target oncogenes that are not protein kinases or ligand- dependent transcription factors, resistance due to clonal evolution and tumor heterogeneity, and failure to mount an immune response against the tumor. This SPORE renewal focuses on these obstacles by articulating cross- cutting objectives and aligned approaches that increase the efficiency of core utilization and promote inter-project collaboration. The three full Projects include studies on how to target the derepressed kinases consequent upon loss of the PTPN12 or the NF1 tumor suppressors in breast cancer, and the development of a promising new therapeutic approach for MYC-positive breast cancer. During the execution of these Projects we will: a) deploy proteogenomic approaches for monitoring kinase targets and resistance pathways; b) establish high-quality biomarkers for clinical trial eligibility and stratification; c) investigate disease-monitoring approaches with circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA); d) incorporate immunological approaches into treatment regimens by increasing the quality and quantity of tumor infiltrating lymphocytes; e) embed our SPORE biomarker program into early phase clinical trials to inform the design of Phase 3 trials; and f) promote collaborative research between Academia, NCI-Supported Cooperative Groups, Industry, and Advocacy Groups. These objectives are served by three reformatted Cores, with the addition of a dedicated and highly-qualified molecular research pathologist for the Pathology and Biobanking Core, the addition of deeper bioinformatics expertise to the Informatics and Biostatistics Core, and a new SPORE director plus additional advocates and advisory board members for the Administration Core. The Career Enhancement and Developmental Research Programs will be guided by highly experienced leadership and, as before, will cement the future of our SPORE. With this powerful enhanced program we will advocate nationally for progress in the treatment of advanced breast cancer, with the conviction that a cure is a near-term possibility.